Non-insulin dependent diabetes mellitus (NIDDM) is associated with both insulin resistance and abnormal B-cell function, but which of these factors is primary is not known. Many persons with insulin resistance associated with obesity or pregnancy maintain normal glucose tolerance while others develop hyperglycemia. We hypothesize that persons with normal B-cell adaptation to insulin resistance will increase insulin output in response to insulin resistance and maintain normoglycemia whereas persons with abnormal B-cell adaptation may develop diabetes. The long-term objective of this project is to evaluate the importance of abnormal B-cell adaptation in the development of NIDDM, and to better understand the physiology of this adaptation. The proposed research will measure the increase in B-cell function to nicotinic acid-induced insulin resistance in two groups at high risk for developing NIDDM: (1) normoglycemic women who developed gestational diabetes mellitus during a previous pregnancy, and (2) subjects with a positive family history of NIDDM. A significant decrease i the degree of B-cell adaptation when compared to a matched control group would suggest that B-cell maladaptation is an important factor in the development of NIDDM. In addition, to better understand the physiology of B-cell adaptation, the time course of changes in several metabolic parameters will be determined in normal subjects during the development of nicotinic acid- induced insulin resistance. These parameters include plasma glucose, insulin, and free fatty acid (FFA) levels, insulin resistance, and B-cell function. A further interventional study will evaluate whether insulin resistance-induced elevation of glucose levels is a signal for B-cell adaptation. For this study, exogenous insulin will be given to human subjects to counteract the mild glucose elevations that occur with insulin resistance. Finally, to elucidate the mechanism(s) for nicotinic acid- induced insulin resistance, tritiated glucose will be used to determine whether nicotinic acid acts on the liver or on other peripheral tissues such as muscle and fat. Additionally, nicotinic acid is hypothesized to cause insulin resistance from a rebound of FFA levels between doses. To evaluate this hypothesis and to assess the role of elevated FFA in the development of insulin resistance, the degree of insulin resistance will be measured in human subjects while taking either pulsed or continuous doses of nicotinic acid. The proposed research will be performed in the clinical research facilities at the Seattle VA Medical Center and University of Washington and in the laboratory of Dr. Daniel Porte Jr.